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Agent for suppressing development of tolerance to narcotic analgesics

a technology of narcotic analgesics and agents, which is applied in the field of drugs for suppressing the development of tolerance to narcotic analgesics, can solve the problems of not being able to report on the effectiveness of vsub>1b /sub>receptors, many functions of vsub>1b /sub>receptors remain unrevealed, and the action of suppressing the development of tolerance to analgesi

Inactive Publication Date: 2010-01-07
KYOTO UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a medicament that can prevent the development of tolerance to narcotic analgesics such as morphine. This is achieved by using an antagonist of the vasopressin receptor, specifically the V1b receptor. The medicament can be used in combination with a narcotic analgesic or separately. The invention also provides a method for suppressing the development of tolerance to narcotic analgesics by administering the vasopressin receptor to a mammal.

Problems solved by technology

However, any medicament having superior effectiveness has not yet been clinically developed.
However, many functions of the V1b receptor remain unrevealed.
Further, no report has been made to date that teaches involvement of the V1b receptor in the development of tolerance to narcotic analgesics.
However, these publications do not suggest or teach that these compounds suppress the development of tolerance to narcotic analgesics.
However, many functions of the V1b receptor remain unrevealed.
Further, no report has been made to date that teaches involvement of the V1b receptor in the development of tolerance to narcotic analgesics.
However, these publications do not suggest or teach that these compounds suppress the development of tolerance to narcotic analgesics.

Method used

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  • Agent for suppressing development of tolerance to narcotic analgesics
  • Agent for suppressing development of tolerance to narcotic analgesics
  • Agent for suppressing development of tolerance to narcotic analgesics

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0030]V1a receptor knockout mice (Neuroscience Letters, 356, pp. 195-198, 2004), V1b receptor knockout mice (J. Clin. Invest., 113, pp. 302-309, 2004), and control mice (body weight: about 30 g) were subcutaneously (s.c.) given with 10 mg / kg of morphine hydrochloride once a day, which was repeated for 15 days. The analgesic effect was evaluated by the tail-flick test on 1st, 5th, 9th, 12th and 15th days after the administration on the basis of the maximal possible effect (% MPE), which represents analgesic intensity and is calculated in accordance with the following equation.

% MPE=100×[(Measured value after treatment−Measured value before treatment)+(Cut-off value−Measured value before treatment)]

[0031]As a result, it was found that tolerance to morphine was developed in the V1a receptor knockout mice and the control mice, whereas remarkable resistance against tolerance to morphine was observed in the V1b receptor knockout mice. The results are shown in FIG. 1. These results suggest...

example 2

[0032]Male ddY mice (5- or 6-week old) were intracerebroventricularly (i.c.v.) given with 5 μl of physiological saline or a V1 receptor antagonist (0.5, 5 or 10 ng), and immediately after the administration, the mice were subcutaneously given with 10 mg / kg of morphine hydrochloride, which was repeated twice a day for 5 days to induce tolerance to morphine analgesic. The analgesic effect was evaluated by the tail-flick test on 1st, 3rd and 5th days after the administration on the basis of intensity of analgesic effect using % MPE and AUC (area under the time-reaction curve, Area Under the Curve). As the V1 receptor antagonist, the following three types of antagonists were used.

[0033](a) PhAcALVP ([phenylacetyl, O-Me-D-Try, Arg, Lys]-vasopressin amide):

[0034]Antagonist highly selective to the V1a receptor

[0035](b) d(CH2)5Tyr(Me)AVP ([β-mercapto-β,β-cyclopentamethylenepropionyl, O-Me-Tyr, Arg]-vasopressin): Antagonist of the V1a receptor

[0036](c) dPenTyr(Me)AVP (deamino-Pen, O-Me-Tyr, ...

example 3

[0040]Effect on development of tolerance to morphine-induced analgesic effect was examined by using an antagonist selective to the V1b receptor, (2S,4R)-1-[5-chloro-1-[2,4-dimethoxyphenyl]sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine carboxamine (SSR149415, The Journal of Pharmacology Experimental Therapeutics, 300, pp. 1122-1130, 2002). In combination with morphine (10 mg / kg, s.c.), ddy mice were given with a solvent (1% DMSO in physiological saline, i.c.v.) or a V1b antagonist (i.c.v.) twice a day (at 9:00 and 17:00) for 4 days. The analgesic effect was determined by the tail-flick test (TailFlick Unit, UgoBasile, Milano, Italy). The analgesic effect of morphine (10 mg / kg, s.c.) was observed after the first administration of morphine on the 1st, 3rd, and 5th days. Intensity of the heat source was set so that the reference reaction time became 2 or 3 seconds. Cut-off time was set to be 10 seconds so that possible damage to the c...

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Abstract

A medicament for suppressing development of tolerance to analgesic effect induced by administration of a narcotic analgesic such as morphine, which comprises an antagonist of the vasopressin receptor 1b as an active ingredient.

Description

[0001]The present application is a continuation of U.S. application Ser. No. 11 / 722,833 filed Dec. 26, 2005, the disclosure of which is expressly incorporated by reference herein in its entirety.TECHNICAL FIELD [0002]The present invention relates to a medicament for suppressing development of tolerance to a narcotic analgesic such as morphine.BACKGROUND ART [0003]Since narcotic analgesics such as morphine have superior analgesic effect on visceral pain and the like, they have been clinically used for pain treatment of patients with terminal cancer. However, prolonged administration of narcotic analgesics rapidly induces tolerance to the analgesic effect as their primary action. Therefore, careful control of administration frequency and dose thereof is required to minimize the development of tolerance while achieving desired analgesic effect. As agents for suppressing development of tolerance to narcotic analgesics, for example, medicaments described in International Patent Publicat...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/485
CPCA61K31/404A61K31/485A61K38/11A61K45/06A61K2300/00A61K38/095A61P25/04A61P25/20A61P43/00
Inventor TSUJIMOTO, GOZOHTAKANO, YUKIOHONDA, KENJITANOUE, AKITO
Owner KYOTO UNIV
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